Metabolic diseases in general and Type II diabetes [(T2DM or T2D or Type II Diabetes or Non-insulin dependent mellitus (NIDDM)] in particular are a complex, multigene and multifactorial disease. Metabolic diseases such as hyperlipidemia, obesity and hypertension as well as environmental factors contribute to this disease. Cardiometabolic risk factor clusters (CMRFC) such as diabetes, hyperlipidemia, hypertension and overweight/obesity often cluster together in the same individual (Garber, A. J. et al. 2013). The prevalence of these risk factors is increasing significantly for all sociodemographic groups and it is putting an enormous economic burden on the society. Currently over one-fourth (over 70 million) of the U.S. population live with cardiovascular (CV) disease along with cardiometabolic risk factors. The economic impact of CV disease is enormous. In 2005, it was estimated to be over $242 B in direct medical expenses and over $152 B in indirect medical costs including lost productivity, resulting in a total estimated cost of $395 B in the U.S. alone (Sullivan, P. W. et al. 2007). CV disease is the leading cause of death resulting in an estimated 40% (>840,000) of all the deaths. Over 225 million people worldwide and over 26 million people in the USA alone suffer from Type II diabetes. In 2013, the annual cost of clinical management of this disease was over $245 B ($176 B for direct medical costs and $69 B in reduced productivity) (Statistics about diabetes, ADA, 2014). Type II diabetes was the seventh leading cause of death in the U.S. in 2010 (Mortality data, 2010, CDC). According to GB Research (Global Business Intelligence), the global Type II diabetes market will grow from $20.4 B in 2012 to $38.8 B in 2019. The U.S. market will more than double, from $12.7 B in 2012 to $27.2 B in 2019 (GBI Research, 2013). The world market for metabolic syndrome is estimated to be $72.4 B by 2018 (biovision.com).
Insulin resistance is a pathological hallmark of metabolic syndrome in general and Type II diabetes in particular. Type II diabetes continues to be an unmet medical need due to a number of factors including: the idiopathic nature of the disease, complex pathophysiology attributed to auto-immune and pro-inflammatory components, and comorbidities such as hyperlipidemia, obesity and high blood pressure (Erik, P. et al. 2009). Complexity of the disease contributes to manifestation of T2DM in multiple and diverse pathophysiological conditions such a way that the disease constitutes a unique pathophysiological phenomenon in each patient. Complexity of the disease in combination with unique metabolic profile and life style of each patient or group of patients contribute to lack of adequate efficacy with currently marketed Type II diabetes drugs (American College of Physicians, 2012). Moreover, Type II diabetes patients who are on current treatment regimens, continue to be vulnerable for complications such as diabetic retinopathy, skin ulcers, risk of coronary heart disease (CHD), stroke, chronic kidney disease (CKD), diabetic peripheral neuropathy, diabetic vasculopathy etc.
Type II diabetes continues to be an unmet medical need and at the current rate, it will double to over 640 million T2D patients world-wide by 2030 (American Diabetes Association). It is characterized by progressive deterioration of pancreatic beta cell dysfunction and insulin resistance. In spite of intense treatment with mono- and combination therapies with the existing modalities, patients suffer from progressive deterioration of metabolic control of glucose homeostasis (Standards of Medical Care in Diabetes, 2015). Lack of adequate glycemic control as indicated by inability to reach the target glycemic (A1c), blood pressure and cholesterol levels with currently marketed standards of medical care for Type II diabetes puts patients on a certain path to develop diabetes-related complications such as stroke, retinopathy, neuropathy, nephropathy, and skin ulcers. With the guidelines recommended by the American Association of Clinical Endocrinologists, 39-49% of patients do not meet targets for glycemic, blood pressure or cholesterol levels (Standards of Medical Care in Diabetes, 2015). It is needless to say that there's a desperate need for new modalities and innovation in the Type II diabetes space.
The complex etiology involves a combination of a variety of inflammation-triggered cellular dysfunctions that contribute individually and collectively to pancreatic cell dysfunction (Tateya, S. et al. 2013). Cyclooxygenase 2 or Cox-2 or COX-II is the predominant mediator of pro-inflammatory PGE2 synthesis in pancreatic islet cells (Robertson, R. P. 1998). ARKAY is advancing an innovative anti-inflammatory pancreatic beta cell-centric platform that treats islet cell dysfunction in combination with insulin resistance. It is well established that signaling pathways associated with immune dysregulation, chronic low-grade inflammation associated with obesity-triggered insulin resistance, and cardiovascular disease are intricately intertwined and they are literally inseparable from each other (Shu, C. J. et al. 2012).
Type II diabetes is characterized by impaired first phase of insulin secretion due to progressive deterioration of pancreatic beta cell function which compromises its inherent capacity to compensate for insulin resistance. Functional response of beta cells and insulin sensitivity of insulin-responsive tissues such as liver and skeletal muscle are tightly regulated by a feed-back loop. The magnitude of beta cell response is directly proportional to the tissue sensitivity of insulin-responsive tissues. This feedback loop determines the normal regulation of glucose metabolism and maintenance of glucose homeostasis. Beta cells have an inherent capacity to compensate with an increased output of insulin when insulin resistance is present. Blood glucose levels rise in the presence of insulin resistance when beta cells are incapable of releasing sufficient insulin due to progressive deterioration of beta cell function.
Activation of inducible Cyclooxygenase, Cox-2 or activation of constitutive Cox-2 plays a critically important role in the initiation of obesity-triggered inflammation. A link between elevation of blood glucose levels and activation of Cox-2 in pancreatic beta cells is well established. High glucose-induced PGE2 causes reduction in the beta cell mass by inhibiting its proliferation as well as induction of apoptosis of beta cells (Oshima, H. et al 2006). Indomethacin, a non-selective Cyclooxygenase inhibitor prevented HFD—(high fat diet)—induced obesity and insulin resistance in C57BL/6J mice (Fjaere E. et al. 2014). Treatment with NSAIDs (Non-steroidal anti-inflammatory drugs) such as Celecoxib and Salsalate have been shown to restore systemic insulin sensitivity in both translational preclinical models as well as in obese patients with T2DM (Goldfine, A. B. et al. 2013; Gonzalez-Ortiz, et al. 2005). High blood glucose activates Cox-2 in pancreatic beta cells and contributes to beta cell dysfunction. Treatment with NS-398 (a selective Cox-2 inhibitor) reverses beta cell dysfunction (Tian, V. F. et al. 2014) presumably by reducing PGE2-mediated beta cell apoptosis. Obesity-triggered inflammation due high blood sugar levels results in non-alcoholic hepatic steatosis which is a pathological hallmark of insulin resistance. Non-alcoholic steatohepatitis (NASH) is a condition that coexists with T2DM. Celecoxib reverses steatohepatitis as well as inflammation in HFD-induced Wistar rat NASH model (Chen, J. et al. 2011). Over-expression of NAG-1/GDF-15 (NSAIDs-activated gene-1) has been shown to improve glycemic parameters and prevent development of obesity by increasing thermogenesis, lipolysis and oxidative metabolism in obese C57BL/6J mice (Chrysovergis, K. et al. 2014). Activation of inducible form of Cox-2 plays a critically important role in the initiation of cellular dysfunctions including: adipocyte dysfunction, pancreatic beta islet cell dysfunction and macrophage dysfunction. Cellular dysfunctions contribute to development of insulin resistance and systemic glucose intolerance. Cox-2 deletion in C57BL/6J obese mice reduces blood glucose levels (Fujta et al. 2007). More importantly, in the same translational preclinical model, selective Cox-2 inhibitor, Celecoxib reduces HbA1c levels, improved glucose tolerance and elevated insulin levels (Fujita, H. et al. 2007). Selective Cox-2 inhibitors such as Celecoxib and Mesulid restore insulin sensitivity, reduce oxidative stress and reverse low-grade inflammation in male Sprague Dawley rats fed with High fructose diet or High fat diet (HFD) (Hsieh, P. et al. 2009; Liu, T. et al. 2009). They both reduced time-dependent increases in plasma insulin, 8-isoprostanes, leptin levels, and reversed increase in hepatic triglycerides. Celecoxib also restored insulin sensitivity in a small study of 12 obese patients (Gonzalez-Ortiz, et al. 2005).
Renin-Angiotensin system (RAS) exists in pancreatic beta cells and Angiotensin II is pro-inflammatory in pancreas and activates pro-inflammatory cytokine IL-1 beta. Ang II-mediated Islet cell inflammation triggers beta cell dysfunction contributing to Pancreatic beta cell exhaustion and decompensation (Sauter, N. et al. 2015). This occurs independent of vasoconstriction because sub-hypertensive dose of Valsartan (1 mg/Kg/day) improves impaired glucose tolerance with no effect on the systolic blood pressure in C57BL/6J obese mice. Blockade of Ang II with an ARB (Angiotensin receptor blocker) such as Valsartan improves glucose tolerance (Cole, B. K. et al. 2010) as well as restores not only beta cell dysfunction but also enhances blood flow as a result of vasodilation. The anti-hypertensive drug Metformin, which is considered the gold standard for the treatment of T2DM ameliorates not only HFD-induced insulin resistance but also improves glucose tolerance in C57BL/6J diet-induced obesity (DIO) model (Matsui, Y. et al. 2010; Woo, S. et al. 2014).
A number of publications have supported the importance of adipocytes and inflammation for the development of insulin resistance. For example, JNK-1 deficiency in adipocytes suppressed HFD—(High fat diet)—induced insulin resistance in the liver due to suppression of JNK-dependent suppression of IL-6 (Sabio, C. et al. 2008), adipocyte-specific deletion of Glut4 or over expression of MCP-1 results in systemic insulin resistance (Qi, L. et al. 2009), TNF-alpha deficiency improved insulin sensitivity in diet-induced obesity and in Lep ob/ob model of obesity and neutralization of TNF-alpha in obese fa/fa rats ameliorated insulin resistance (Hotamisiligil, G. S. et al. 1995). Elevated IL-1 beta, IL-6 and CRP are predictive of development of T2DM (Visser, M. et al. 1999) and TLR4 knock-out mice were protected from inflammation and insulin resistance (Shi, H. et al. 2006). Therefore, the lack of adequate efficacy and lack of adequate overall clinical benefit from currently marketed anti-hyperglycemic drugs is due to their inability to suppress the pro-inflammatory components of the complex pathophysiology of initiation and maintenance of systemic insulin resistance. TZDs and statins do have an inherent yet very modest anti-inflammatory capacity which contributes to their therapeutic efficacy. Therefore, suppression of obesity-triggered chronic low-grade inflammation with an anti-inflammatory drug such as Cox-2 selective inhibitor is anticipated to treat the impaired glucose homeostasis in T2DM patients by enhancing the efficacy of anti-hyperglycemic drugs with an additive or synergistic effect. Inhibition of inflammation is also anticipated to reduce the severity of diabetes-related complications.
Inflammation is a critical component of the pathophysiology of not only Type II diabetes but also the clinically relevant comorbidities as illustrated in FIG. 2. More importantly, pro-inflammatory signals contribute to initiation and maintenance of complications associated with Type II diabetes such as diabetic retinopathy, skin ulcers, risk of coronary heart disease (CHD), stroke, chronic kidney disease (CKD), diabetic peripheral neuropathy, diabetic vasculopathy etc. Pro-inflammatory signals determine the severity and duration of diabetes-related complications. An anti-inflammatory drug, Salsalate has been shown to reduce glycosylated hemoglobin A1c by an average of 0.37% in a clinical study conducted by Harvard Medical School (Goldfine, A. et al. 2013). There is a direct correlation between elevation in the pro-inflammatory biomarkers and impaired glucose metabolism. Statins and Thiazolidinediones (TZDs) reduce the risk of developing diabetes by consistently lowering the inflammatory markers (Deans K. A. and Sattar, N. (2006). Therefore, for efficient clinical management, it is important to treat cardiometabolic diseases including Type II diabetes not as an individual disease but as a metabolic syndrome with a complex pathophysiology with a strong pro-inflammatory component. For example, to achieve sufficient therapeutic efficacy in Type II diabetes patients who present wide-ranging challenges and metabolic profiles, it is indeed necessary to treat with a pro-inflammatory-centric combination of drugs that correct not only the impaired glucose homeostasis but also attenuate clinically relevant comorbidities and more importantly reduce the severity of diabetes-related complications. Instead of treating patients with metabolic syndrome as one homogeneous population with just one drug, it is necessary to treat patients with an anti-inflammatory drug in combination with anti-metabolic disease drugs with known efficacy and safety profile.
Patients stratified into groups for lack of adequate clinically favorable response to currently marketed drugs to treat metabolic diseases will be selected to test different Fixed Dose Combinations (FDC) formulations. Combination of drugs custom-formulated to provide therapeutic benefit to a specific stratified group of patients is anticipated to have therapeutic as well as kinetic synergy. More importantly these drugs would block the pro-inflammatory components of some of the comorbidities as well as attenuate the severity of complications such as Chronic kidney disease, diabetic neuropathy, diabetic nephelopathy, skin ulcers etc. Inclusion of an anti-inflammatory drug in every potential FDC formulation would result in enhancing therapeutic efficacy of Type II diabetes drugs by reducing therapeutic dose range such as minimal effective dose (MED), maximal tolerated dose (MTD) as well as the maintenance dose. Therefore, blockade of the pro-inflammatory components would contribute to sparing or reducing the severity or duration of some of the adverse side effects. Pro-inflammatory-centric anti-metabolic syndrome FDC formulations would result in the development of drugs that differentiate clinically as well as mechanistically from the currently available drugs.
The prevalence of prediabetes is 3 times more than that of Type II diabetes. American Diabetes Association reported that in 2012, there were 86 million Americans 20 or older had prediabetes (Statistics about diabetes, ADA, 2014). Insulin resistance as a result of failing pancreatic compensation due to excessive body weight or obesity, impaired glucose tolerance, impaired fasting glucose and symptomatic metabolic syndrome are the pathological hallmarks of prediabetes (American College of Physicians, 2012). Currently, there are no drugs that prevent or delay progression of prediabetes into insulin resistance or metabolic syndrome or incidence or new-onset T2DM.
Renin-Angiotensin System (RAS) exists in the pancreatic islets (Leung, P. S. 2012; Andraws, R. and D. L. Brown, 2007). Blockade of the RAS particularly with Angiotensin II receptor blockers (ARBs) and ACE (Angiotensin-converting enzyme) inhibitors has been shown to prevent the incidence or onset of Type II diabetes in patients with impaired glucose tolerance (IGT) (Van der Zijl, N. R. et al. 2011). Moreover, in normotensive patients with impaired glucose tolerance, ARBs increase glucose-dependent insulin secretion and enhance insulin sensitivity (McMurray, et al. 2010). Anti-inflammatory FDC formulations that combine anti-type II diabetes drugs with ARBs and ACE inhibitors will have tremendous therapeutic potential in terms of reducing the number of prediabetes patients who are on a certain path to positive clinical diagnosis for Type II diabetes.
It is hypothesized that in normotensive prediabetes and Type II diabetes, Anti-inflammatory FDC formulations that includes sub-therapeutic doses of ARBs and ACE inhibitors would enhance therapeutic efficacy of Type II diabetes drugs by reducing therapeutic dose range [minimal effective dose (MED), maximal tolerated dose (MTD) and the maintenance dose]. Therefore, blockade of the pro-inflammatory and RAS components would contribute to sparing or reducing the severity or duration of some of the adverse side effects associated with Type II diabetes drugs.
There is a continuing need for compounds, compositions, formulations and methods to treat metabolic syndrome.